Osteoarthritis (OA) is one of the most common illness in man. The frequency of 0A in the general population is estimated to be as great as 35% in the 30-40 year old age group and the frequency may rise to as much as 85% in individuals greater than 70 years of age. 0A is also a significant cause of work absenteeism and a significant cause of disability. Furthermore, 0A represents a significant burden to the health care system because of the extensive consultation with physicians and the use of medication needed to treat the disease. In this proposal, we intend to define genetic factors that contribute to 0A and degenerative joint disease. our initial studies will concentrate on disease present in a large New England family with both chondrocalcinosis and severe degenerative OA. In this family, disease appears to be inherited in an autosomal dominant fashion suggesting a strong genetic component being responsible for the disease. Using genetic linkage experiments, we established linkage between disease and human chromosome 8q in this family. Our specific aims are designed to use genetic linkage experiments to further refine the location of the gene for disease in this family. We will then obtain DNA clones for the candidate region and search for genes that, when defective, cause disease. We will then sequence the defective gene to determine the exact cause of disease. We will then extend our findings to test the hypothesis that this gene, and others that we may find, play important roles in common forms of 0A. In addition, the results of this study will define the exact role these genes play in cartilage and establish why defects in their expression result in disease. It will also permit the exact diagnosis of the disease and help us understand existing animal models for OA. In addition, information derived from our work will provide the basis for developing better animal models in which new therapies can be tested and the pathogenesis of the disease be followed.